Published online before print March 27, 2008, doi: 10.1161/CIRCRESAHA.107.164749
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 21, 2007
Revised on February 29, 2008
Accepted on March 13, 2008
Activation of Notch-Mediated Protective Signaling in the Myocardium
Natalie A. Gude ;
From the San Diego State University Heart Institute (N.A.G., G.E., W.W., C.T.C., K.F., P.Q., J.A.M., R.A., M.R., M.A.S.), Department of Biology, San Diego State University, Calif; and Biosource International (E.S.), Hopkinton, Mass.
* To whom correspondence should be addressed. E-mail: sussman{at}heart.sdsu.edu.
The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. These processes are regulated via Notch-mediated activity that involves hepatocyte growth factor (HGF)/c-Met receptor and phosphatidylinositol 3-kinase/Akt signaling cascades. The impact of HGF on Notch signaling was assessed following myocardial infarction well as in cultured cardiomyocytes. Notch1 is activated in border zone cardiomyocytes coincident with nuclear c-Met following infarction. Intramyocardial injection of HGF enhances Notch1 and Akt activation in adult mouse myocardium. Corroborating evidence in cultured cardiomyocytes shows treatment with HGF or insulin increases levels of Notch effector Hes1 in immunoblots, whereas overexpression of activated Notch intracellular domain prompts a 4-fold increase in phosphorylated Akt. Infarcted hearts injected with adenoviral vector expressing Notch intracellular domain treatment exhibit improved hemodynamic function in comparison with control mice after 4 weeks, implicating Notch signaling in a cardioprotective role following cardiac injury. These results indicate Notch activation in cardiomyocytes is mediated through c-Met and Akt survival signaling pathways, and Notch1 signaling in turn enhances Akt activity. This mutually supportive crosstalk suggests a positive survival feedback mechanism between Notch and Akt signaling in adult myocardium following injury.
Key words: Notch • Akt • cardioprotection • infarction • myocardium
This article has been cited by other articles:
 |
|
 |
|
  R. Whittaker, M. S. Glassy, N. Gude, M. A. Sussman, R. A. Gottlieb, and C. C. Glembotski Kinetics of the translocation and phosphorylation of {alpha}B-crystallin in mouse heart mitochondria during ex vivo ischemia Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1633 - H1642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Croquelois, A. A. Domenighetti, M. Nemir, M. Lepore, N. Rosenblatt-Velin, F. Radtke, and T. Pedrazzini Control of the adaptive response of the heart to stress via the Notch1 receptor pathway J. Exp. Med., December 22, 2008; 205(13): 3173 - 3185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tadimalla, P. J. Belmont, D. J. Thuerauf, M. S. Glassy, J. J. Martindale, N. Gude, M. A. Sussman, and C. C. Glembotski Mesencephalic Astrocyte-Derived Neurotrophic Factor Is an Ischemia-Inducible Secreted Endoplasmic Reticulum Stress Response Protein in the Heart Circ. Res., November 21, 2008; 103(11): 1249 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Boni, K. Urbanek, A. Nascimbene, T. Hosoda, H. Zheng, F. Delucchi, K. Amano, A. Gonzalez, S. Vitale, C. Ojaimi, et al. Notch1 regulates the fate of cardiac progenitor cells PNAS, October 7, 2008; 105(40): 15529 - 15534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Siddiqi, N. Gude, T. Hosoda, J. Muraski, M. Rubio, G. Emmanuel, J. Fransioli, S. Vitale, C. Parolin, D. D'Amario, et al. Myocardial Induction of Nucleostemin in Response to Postnatal Growth and Pathological Challenge Circ. Res., July 3, 2008; 103(1): 89 - 97. [Abstract] [Full Text] [PDF]
|
|